Elysia A. Masters, Ryan P. Trombetta, Karen L. de Mesy Bentley
et al.
AbstractOsteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high.Staphylococcus aureusis responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including:Staphylococcalabscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast,S. aureusintracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome againstS. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.
A unified consensus statement on medication-related osteonecrosis of the jaw (MRONJ) has not yet been established among the Asian member countries or regions of the Asian Federation of Osteoporosis Societies (AFOS). This study aimed to develop a consensus on MRONJ in patients with osteoporosis across these countries and regions. In this study, the term “Asia-Pacific” refers specifically to the Asian member countries and regions of AFOS. A structured survey consisting of nine MRONJ-related questions was distributed across 10 countries and regions to assess the level of agreement and summarize regional perspectives. In addition, a manual literature review and voting were conducted to evaluate the current evidence on MRONJ. The key aspects of MRONJ, including definition, staging, diagnosis, pathogenesis, risk factors, management, and prevention, were generally consistent among the AFOS countries and regions. The annual incidence and incidence rate of MRONJ associated with low-dose antiresorptive therapy in patients with osteoporosis ranged from 0.025% to 0.136% and 21 to 283 cases per 100,000 person-years, respectively. However, evidence regarding the benefits of drug discontinuation before dental surgery, such as tooth extraction, remains insufficient. Large-scale, multinational studies across AFOS countries and regions are warranted to determine the incidence of MRONJ better and evaluate the impact of antiresorptive drug discontinuation before dental procedures. These findings may contribute to the development of effective evidence-based strategies for preventing MRONJ in patients with osteoporosis.
Anil Kumar Kotteda, Abhishek Chaudhary, Arjit Bansal
et al.
Introduction:
Fungal musculoskeletal infections are rare and often present diagnostic and therapeutic challenges, particularly in immunocompromised individuals. Phaeohyphomycosis is a dematiaceous fungal infection with a wide clinical spectrum, but isolated prepatellar bursitis due to this organism has not been previously reported. This case highlights the importance of maintaining a high index of suspicion for unusual pathogens in transplant recipients presenting with atypical joint or periarticular infections.
Case Report:
We report the case of a 55-year-old female renal transplant recipient on long-term immunosuppressive therapy who presented with progressive swelling and pain over the anterior aspect of the knee. Clinical examination revealed localized swelling consistent with prepatellar bursitis, with no systemic features of infection. Initial aspiration yielded dark-colored fluid, and microscopy demonstrated pigmented fungal elements. Fungal culture confirmed the diagnosis of phaeohyphomycosis. The patient underwent surgical bursectomy followed by antifungal therapy, with gradual resolution of symptoms. At the latest follow-up, she remained asymptomatic with no evidence of recurrence.
Conclusion:
This case underlines the need for early recognition of unusual infectious agents in immunosuppressed patients with persistent musculoskeletal complaints. Isolated fungal bursitis due to phaeohyphomycosis is extremely uncommon, and timely surgical intervention combined with appropriate antifungal therapy is critical for favorable outcomes. Orthopedic surgeons should be aware of this rare entity, as prompt diagnosis and multidisciplinary management can prevent morbidity and preserve function.
Orthopedic surgery, Diseases of the musculoskeletal system
Garazi Retegui, María Dolores Ugarte, Jaione Etxeberria
et al.
To date, we have seen the emergence of a large literature on multivariate disease mapping. That is, incidence of (or mortality from) multiple diseases is recorded at the scale of areal units where incidence (mortality) across the diseases is expected to manifest dependence. The modeling involves a hierarchical structure: a Poisson model for disease counts (conditioning on the rates) at the first stage, and a specification of a function of the rates using spatial random effects at the second stage. These random effects are specified as a prior and introduce spatial smoothing to the rate (or risk) estimates. What we see in the literature is the amount of smoothing induced under a given prior across areal units compared with the observed/empirical risks. Our contribution here extends previous research on smoothing in univariate areal data models. Specifically, for three different choices of multivariate prior, we investigate both within prior smoothing according to hyperparameters and across prior smoothing. Its benefit to the user is to illuminate the expected nature of departure from perfect fit associated with these priors since model performance is not a question of goodness of fit. We propose both theoretical and empirical metrics for our investigation and illustrate with both simulated and real data.
Abstract Background Meniscus tears can change the biomechanical environment of the knee joint and might accelerate the development of osteoarthritis. The aim of this study was to investigate the dynamic biomechanical effects of different medial meniscus tear positions and tear gaps on the knee during walking. Methods Seven finite element models of the knee joint were constructed, including the intact medial meniscus (IMM), radial stable tears in the anterior, middle, and posterior one-third regions of the medial meniscus (RSTA, RSTM, RSTP), and the corresponding unstable tears (RUTA, RUTM, RUTP). The seven models applied a 1000 N axial static load and a human walking load, as defined by the ISO14243-1 standard. Results Compared with the results under static loading, the axial load ratio of the medial and lateral compartments was redistributed (ranging from 0.7:1 to 2.9:1). The stress concentration was in the middle and posterior portions of the lateral compartment, not in the anterior and middle portions of the medial compartment under dynamic analysis. Compared with that of the IMM, the maximum von Mises stress on the medial meniscus increased by approximately 24.68–57.14% in the RUTA, RUTM, and RSTM models, with a greater difference observed in the hoop stress on both sides of the radial tear. The peak radial tear gap appeared at GC6 and GC44, and the tear gap remained at a high level from GC30-GC60. Conclusions Radial tears should be considered for repair, and reinforced sutures should be placed on the anterior or middle regions of the meniscus. Greater attention should be given to the dynamic biomechanical effects on the knee joint during preoperative diagnosis and postoperative rehabilitation.
Orthopedic surgery, Diseases of the musculoskeletal system
H. Mark Kenney, Kiana L. Chen, Lindsay Schnur
et al.
Background Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement. Herein, we sought to determine the particular hindpaw bones that represent reliable biomarkers of sex-dependent disease progression to guide future investigation and analysis. Methods Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2–5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm. Results First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p<0.05). Specifically, the cuboid showed significantly reduced bone volumes at early timepoints compared to other tarsals (i.e., 4-months: Cuboid -24.1±7.2% vs Talus -9.0±5.9% of 2-month baseline). Additional bones localized to the anterolateral region of the ankle also exhibited dramatic erosions in the tarsal region of females, coinciding with increased synovitis and osteoclasts. In TNF-Tg male mice with severe arthritis, the talus and calcaneus exhibited the most sensitive response to anti-TNF therapy measured by effect size of bone volume change over treatment period. Conclusions We demonstrated that sexually dimorphic changes in arthritic hindpaws of TNF-Tg mice are bone-specific, where the cuboid serves as a reliable early biomarker of erosive arthritis in female mice. Adoption of automated segmentation approaches in pre-clinical or clinical models has potential to translate quantitative biomarkers to monitor bone erosions in disease and evaluate therapeutic efficacy.
Abstract Background To analyze and compare the biomechanical characteristics of the new combined cervical fusion device (NCCFD) and the traditional cage-plate construct (CPC) to ascertain its effectiveness in anterior cervical discectomy and fusion (ACDF) using finite element analysis. Methods A finite element model of the cervical spine, inclusive of the occipital bone was created and validated. In the ACDF model, either CPC or NCCFD was implanted at the C2–C3 segment of the model. A pure moment of 1.0 Nm combined with a follower load of 50 N was directed onto the superior surfaces of the occipital bone to determine flexion, extension, lateral bending (left and right), and axial rotation (left and right). The range of motion (ROM), stress distribution at the bone-implant interface, and facet joint forces were investigated and compared between CPC and NCCFD systems. Result The results showed that the ROMs of the fused levels in both models were nearly zero, and the motions of the unfused segments were similar. In addition, the maximum displacement exhibited nearly identical values for both models. The maximum stress of NCCFD screws in lateral bending and rotational conditions is significantly higher than that of the CPC, while the NCCFD model’s maximum stress remains within an acceptable range. Comparing the maximum fusion stress, it was found that the CPC experiences much lower fusion stress in anterior flexion and extension than the NCCFD, with no significant difference between the two in lateral bending and rotational states. Stress on the cage was mainly concentrated on both sides of the wings. Comparing the maximum IDP in the CPC and NCCFD, it was observed that maximum stresses rise in extension and lateral bending for both models. Lastly, stress distributions of the facet joints were generally similar across the two devices. Conclusion NCCFD not only provides the same level of biomechanical stability as CPC but also avoids postoperative complications associated with uneven force damage to the implant. The device offers a novel surgical alternative for ACDF in C2–C3 level.
Orthopedic surgery, Diseases of the musculoskeletal system
Abstract Background This study investigates the incidence of ocular involvement in Kawasaki disease (KD) and evaluates the relationship between ocular manifestations, laboratory findings, echocardiographic findings, and intravenous immunoglobulin (IVIG) resistance. Methods We conducted a cross-sectional study with 58 KD patients from June 2021 to March 2023. For all patients, a complete ophthalmologic examination and echocardiography were performed in the acute phase before starting the treatment. We analyzed the age, sex, mean of white blood cell (WBC) count, platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), echocardiographic findings and IVIG responses for all patients and compared the group with ocular involvement with the group without involvement. Results The incidence of bilateral acute conjunctivitis was 70.7%, while that of acute uveitis was 30%. Patients with uveitis had significantly higher rates of Coronary artery dilatation and IVIG resistance, as well as higher mean levels of WBC, platelet, and CRP compared to those without uveitis. (P < 0.05). Additionally, the age of patients with uveitis involvement was lower than those without involvement. No significant relationships existed between ESR, AST, or ALT values and uveitis (P > 0.05). Furthermore, no significant correlations existed between any examined items and acute bilateral conjunctivitis. Conclusion Uveitis in KD is significantly associated with coronary artery dilatation, IVIG resistance, higher WBC count, platelet count, and CRP level.
Pediatrics, Diseases of the musculoskeletal system
Mounib M. Sabounji, Aïssatou Ndiaye, Saïdou Diallo
Abstract Background Enthesitis/spondylitis-related arthritis (ERA) is a type of juvenile idiopathic arthritis (JIA) frequently associated with HLA-B27. In sub-Saharan Africa, HLA-B27-positive ERA hasn’t been the subject of a specific study. Objectives We aimed to describe the clinical features, disease activity, functional disability and treatment of HLA-B27-positive ERA at diagnosis in Senegal and compare the findings to other populations. Methods We conducted a retrospective study by reviewing the medical records of patients diagnosed with ERA with an age of symptom onset < 18 years according to the 2019 PRINTO provisional criteria for ERA from January 2012 to December 2022. We collected demographic, clinical, paraclinical and therapeutic data. Disease activity score was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional disability was assessed using Bath Ankylosing Spondylitis Functional Index (BASFI). Results A total of 31 patients with HLA-B27-positive ERA were included. Twenty of 31 (64.5%) were males. Twenty-seven (87%) were Fula (ethnicity). The median age at symptom onset and at diagnosis was 12 years and 19 years, respectively. Seven patients had a family history of Spondyloarthritis. Peripheral arthritis and enthesitis were the most common presenting features at disease onset. Peripheral arthritis was present in 29 (93.5%) and located in the lower limbs in 27/29 (93.1%) patients. Heel enthesitis was present in 26 (83.8%) patients. Axial involvement was present in 27 (87%) patients, dominated by low back pain and sacroiliac pain/ buttock pain in 24 (88.8%) and 22 (81.5%) patients, respectively. Seven (22.5%) patients had anterior uveitis. The ESR and CRP were elevated in 65.5% and 57.1% of cases, respectively. On imaging, sacroiliitis was found in 22 patients. The mean BASDAI was 5.5/10 (77.2% of patients had a high active disease; BASDAI ≥ 4/10). The mean ASDAS-ESR/CRP was 3.8. The mean BASFI was 5.4/10 (80% of patients had high functional disability; BASFI ≥ 4/10). Twenty-seven (87%) patients were treated with methotrexate and non-steroidal anti-inflammatory drugs. After 6 months of treatment, mean BASDAI was 3/10 and mean BASFI was 2.5/10. Conclusion In our study, HLA-B27-positive ERA was found in our Senegalese cohort mainly in adolescents of the Fula ethnic group. 22 (70.9%) patients developed ankylosing spondylitis at adulthood. The disease was very active at the time of diagnosis with significant functional disability. Treatment was mainly based on methotrexate and NAISDs.
Pediatrics, Diseases of the musculoskeletal system
Early detection of chronic diseases is beneficial to healthcare by providing a golden opportunity for timely interventions. Although numerous prior studies have successfully used machine learning (ML) models for disease diagnoses, they highly rely on medical data, which are scarce for most patients in the early stage of the chronic diseases. In this paper, we aim to diagnose hyperglycemia (diabetes), hyperlipidemia, and hypertension (collectively known as 3H) using own collected behavioral data, thus, enable the early detection of 3H without using medical data collected in clinical settings. Specifically, we collected daily behavioral data from 629 participants over a 3-month study period, and trained various ML models after data preprocessing. Experimental results show that only using the participants' uploaded behavioral data, we can achieve accurate 3H diagnoses: 80.2\%, 71.3\%, and 81.2\% for diabetes, hyperlipidemia, and hypertension, respectively. Furthermore, we conduct Shapley analysis on the trained models to identify the most influential features for each type of diseases. The identified influential features are consistent with those reported in the literature.
We analyze a disease transmission model that allows individuals to acquire fear and change their behaviour to reduce transmission. Fear is acquired through contact with infected individuals and through the influence of fearful individuals. We analyze the model in two limits: First, an Established Disease Limit (EDL), where the spread of the disease is much faster than the spread of fear, and second, a Novel Disease Limit (NDL), where the spread of the disease is comparable to that of fear. For the EDL, we show that the relative rate of fear acquisition to disease transmission controls the size of the fearful population at the end of a disease outbreak, and that the fear-induced contact reduction behaviour has very little impact on disease burden. Conversely, we show that in the NDL, disease burden can be controlled by fear-induced behaviour depending on the rate of fear loss. Specifically, fear-induced behaviour introduces a contact parameter $p$, which if too large prevents the contact reduction from effectively managing the epidemic. We analytically identify a critical prophylactic behaviour parameter $p=p_c$ where this happens leading to a discontinuity in epidemic prevalence. We show that this change in disease burden introduces delayed epidemic waves.
Lemons and oranges, both are the most economically significant citrus fruits globally. The production of lemons and oranges is severely affected due to diseases in its growth stages. Fruit quality has degraded due to the presence of flaws. Thus, it is necessary to diagnose the disease accurately so that we can avoid major loss of lemons and oranges. To improve citrus farming, we proposed a disease classification approach for lemons and oranges. This approach would enable early disease detection and intervention, reduce yield losses, and optimize resource allocation. For the initial modeling of disease classification, the research uses innovative deep learning architectures such as VGG16, VGG19 and ResNet50. In addition, for achieving better accuracy, the basic machine learning algorithms used for classification problems include Random Forest, Naive Bayes, K-Nearest Neighbors (KNN) and Logistic Regression. The lemon and orange fruits diseases are classified more accurately (95.0% for lemon and 99.69% for orange) by the model. The model's base features were extracted from the ResNet50 pre-trained model and the diseases are classified by the Logistic Regression which beats the performance given by VGG16 and VGG19 for other classifiers. Experimental outcomes show that the proposed model also outperforms existing models in which most of them classified the diseases using the Softmax classifier without using any individual classifiers.
Christo Morison, Małgorzata Fic, Thomas Marcou
et al.
Cooperation arises in nature at every scale, from within cells to entire ecosystems. In the framework of evolutionary game theory, public goods games (PGGs) are used to analyse scenarios where individuals can cooperate or defect, and can predict when and how these behaviours emerge. However, too few examples motivate the transferal of knowledge from one application of PGGs to another. Here, we focus on PGGs arising in disease modelling of cancer evolution and the spread of infectious diseases. We use these two systems as case studies for the development of the theory and applications of PGGs, which we succinctly review and compare. We also posit that applications of evolutionary game theory to decision-making in cancer, such as interactions between a clinician and a tumour, can learn from the PGGs studied in epidemiology, where cooperative behaviours such as quarantine and vaccination compliance have been more thoroughly investigated. Furthermore, instances of cellular-level cooperation observed in cancers point to a corresponding area of potential interest for modellers of other diseases, be they viral, bacterial or otherwise. We aim to demonstrate the breadth of applicability of PGGs in disease modelling while providing a starting point for those interested in quantifying cooperation arising in healthcare.
Gout is a common and disabling form of arthritis. Despite widely available, highly effective, urate-lowering therapies, such as allopurinol, studies continue to demonstrate poor care for individuals with gout in healthcare systems worldwide. In this commentary, we highlight strategies that can be utilised to overcome real-world barriers to optimal gout care, including allied health professional input, patient and clinician education, self-management strategies, and electronic health record solutions.
Jeffrey A Sparks, Yinzhu Jin, Soo-Kyung Cho
et al.
Abstract Objective We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA. Methods We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008–2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes. Results Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD. Conclusions RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors.
Kelly Vogel, Lutfiyya N. Muhammad, Jing Song
et al.
ObjectiveWomen with rheumatoid arthritis (RA) have higher pain and worse functional outcomes compared to men, even when treated with similar medications. The objective of this study was to identify sex differences in pain intensity, pain interference, and quantitative sensory tests (QST), which are independent of inflammation, in patients with RA.MethodsThis study is a post hoc analysis of participants in the Central Pain in Rheumatoid Arthritis cohort. Pain intensity was assessed using a 0–10 numeric rating scale. Pain interference was measured using a Patient‐Reported Outcomes Measurement Information System computerized adaptive test. QST included pressure pain detection thresholds, temporal summation, and conditioned pain modulation. Women and men were compared using multiple linear regression, adjusted for age, education, race, research site, depression, obesity, RA disease duration, swollen joint count, and C‐reactive protein.ResultsMean ± SD pain intensity was 5.32 ± 2.29 among women with RA, compared to 4.60 ± 2.23 among men with RA (adjusted difference 0.83 [95% confidence interval (95% CI) 0.14, 1.53]). Women with RA had lower pressure pain detection thresholds at the trapezius (adjusted difference –1.22 [95% CI –1.73, –0.72]), wrist (adjusted difference –0.57 [95% CI –1.07, –0.06]), and knee (adjusted difference –1.10 [95% CI –2.00, –0.21]). No statistically significant differences in pain interference, temporal summation, and conditioned pain modulation were observed.ConclusionWomen reported higher pain intensity and lower pressure pain detection thresholds (higher pain sensitivity) than men. However, pain interference, temporal summation, and conditioned pain modulation did not differ between men and women.image
Bruna Parreira, Ana Rita Couto, Luís Pinheiro
et al.
Bone formation is a complex process that occurs throughout life, and is normally limited to the skeletal system. In bone formation, osteoprogenitor cells follow several developmental stages, including differentiation in osteoblasts, proliferation, matrix maturation, and mineralization. The mechanisms involved in the mineralization process of bone, such as in the new bone formation, are extremely complex and have been under intense investigation for many years. Bone formation follows two distinct processes, intramembranous and endochondral ossification; both are regulated by signaling pathways involving numerous genes. Disturbance of these signaling pathways may cause a large spectrum of skeletal diseases characterized by new bone formation and bone growth anomalies. This review will only focus on the key genetic pathways involved in heterotopic bone formation. Wingless/integrated (Wnt), hedgehog (HH), and transforming growth factor beta (TGFβ)/bone morphogenetic protein (BMP) signaling pathways are described and illustrated; their relation with new bone formation is demonstrated through their involvement in bone formation disorders.
Paul Emery, Yoshiya Tanaka, Vivian P. Bykerk
et al.
Abstract Introduction One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. Methods The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. Primary endpoint: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). Results Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. Conclusions The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. Trial Registration ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB)